INCREASED pulmonary blood flow may disrupt postnatal lung maturation by altering alveolar, vascular, and immune development. The findings, from a neonatal mouse model, could help explain why pulmonary hypertension linked to congenital heart disease may behave differently in children whose lungs are still developing.
Researchers created an aortocaval fistula in neonatal mice at postnatal day 7 to generate a left-to-right shunt and increased pulmonary blood flow. Lung tissue was then assessed at postnatal days 14 and 30 using RNA sequencing, histology, immunofluorescence, and flow cytometry.
Compared with normal maturation, increased pulmonary blood flow produced substantially greater transcriptomic disruption, with 2,272 differentially expressed genes versus 943 in sham controls. Shared changes involved extracellular matrix organization and cell cycle pathways, while affected lungs showed additional abnormalities in cell cycle regulation and immune signaling.
Histologic findings supported the molecular data. Mice exposed to increased pulmonary blood flow had fewer alveoli at day 14 and continued to show reduced alveolarization at day 30, although alveolar growth continued over time. They also retained more immature double capillary networks, suggesting delayed microcirculatory maturation. Markers of vascular smooth muscle cells and active fibroblasts were increased, consistent with pulmonary vascular remodeling.
The researchers also identified increased CD4+ and CD8+ T cell populations during the active alveolarization period. To test whether immune activation contributed directly to abnormal lung development, mice received cyclosporine A during the early postnatal window.
Treatment reduced alveolar simplification, attenuated vascular remodeling, and improved differentiation of alveolar epithelial cells. These findings suggest that immune activation may be a driver of disrupted maturation rather than simply a downstream response to altered blood flow.
The analysis also identified disrupted circadian and neural pathways, alongside changes in genes including NLRP3, IL23R, Birc5, CENPE, Per2, and Nr1d1. These pathways may represent future therapeutic targets for pediatric pulmonary hypertension associated with increased pulmonary blood flow.
The findings remain preclinical, and differences between mouse and human lung development limit direct translation. Validation in pediatric patient samples will be needed before these mechanisms can inform treatment.
Reference
Zheng S et al. The Postnatal Lung Maturation Disrupted by Increased Pulmonary Blood Flow and Its Clinical Implications. JACC: Asia. 2026;6(8):1532-1549.
Featured Image: Vadim on Adobe Stock.
Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.
